A second class of cannabinergic ligands possessing close similarity with CCs was developed at Pfizer in an effort to simplify the CC structure, while maintaining or improving biological activity (52-56). This group of compounds is generally designated as nonclassical cannabinoids and includes AC-bicyclic (e.g., 26 and 27, Fig. 2) and ACD-tricyclic (e.g., 28, Fig. 2) ligands lacking the pyran Bring of CCs. NCCs share some of the key pharmacophores of the CCs, namely, the phenolic hydroxyl, the side chain, and the northern aliphatic hydroxyl groups. Additionally, this class of cannabinergics has a hydroxypropyl chain on the cyclohexyl ring contiguous and trans to the aromatic phenolic group (e.g., (-)-CP-55,940, 27, Fig. 2). This important new pharmacophore was designated as the southern aliphatic hydroxyl group (3) and has been subjected to extensive investigation by the Makriyannis and Tius groups (46,47,57-60). Synthetic approaches for the SAH group are given in hybrid cannabinoids (Subheading 3.3).
Synthesis of CP-47,497, a ligand that represents the simplest structure in this series, is shown in Scheme 8. The AC-bicyclic nucleus of CP-47,497 was constructed via a cuprous-ion-catalyzed conjugate addition of the Grignard reagent generated from 30 with cyclohexenone. Sodium borohydride reduction of ketone 31 in methanol at low temperature gave a 4:1 ratio of epimeric alcohols 32 and 33. Chromatographic separation of 32 followed by deprotection of the phenolic hydroxyl group led to racemic 26.
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